Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them

ABSTRACT

The present invention relates to bicyclic heterocycles of general formula 
                         
wherein
 
     R a  to R c , A to E and X are defined as in claim 1, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in the treatment of diseases, especially tumoral diseases and diseases of the lungs and airways, and the preparation thereof.

This is a continuation of PCT/EP 00/05547 filed on Jun. 16, 2000, whichclaims benefit to prior U.S. Provisional Application 60/146,644, filedJul. 30, 1999 and prior German Application Nos. DE 199 28 281 and DE 10023 085, filed Jun. 21, 1999 and May 11, 2000, respectively. Benefit ofthe earlier filing date of the prior International Application is herebyclaimed pursuant to 35 U.S.C. § 365(c).

The present invention relates to bicyclic heterocycles of generalformula

the tautomers, the stereoisomers and the salts thereof, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases which have valuable pharmacological properties, particularly aninhibitory effect on signal transduction mediated by tyrosine kinases,the use thereof for treating diseases, particularly tumoral diseases,diseases of the lungs and respiratory tract, and the preparationthereof.

In the above general formula I:

R_(a) denotes a hydrogen atom or a C₁₋₄-alkyl group,

R_(b) denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenylnucleus is substituted in each case by the groups R₁ to R₃, whilst

-   -   R₁ and R₂, which may be identical or different, in each case        denote a hydrogen, fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₃₋₆-cycloalkyl,        C₄₋₆-cycloalkoxy, C₂₋₅-alkenyl or C₂₋₅-alkynyl group,    -   an aryl, aryloxy, arylmethyl or arylmethoxy group,    -   a C₃₋₅-alkenyloxy or C₃₋₅-alkynyloxy group, whilst the        unsaturated moiety may not be linked to the oxygen atom,    -   a C₁₋₄-alkylsulfenyl, C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl,        C₁₋₄-alkylsulfonyloxy, trifluoromethylsulfenyl,        trifluoromethylsulfinyl or trifluoromethylsulfonyl group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms,    -   an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,    -   a cyano or nitro group or an amino group optionally substituted        by one or two C₁₋₄-alkyl groups, wherein the substituents may be        identical or different, or    -   R₁ together with R₂, if they are bound to adjacent carbon atoms,        denote a —CH═CH—CH═CH, —CH═CH—NH or —CH═N—NH group and    -   R₃ denotes a hydrogen, fluorine, chlorine or bromine atom,    -   a C₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group,

X denotes a methine group substituted by a cyano group or a nitrogenatom,

A denotes an imino group optionally substituted by a C₁₋₄-alkyl group,

B denotes a carbonyl or sulfonyl group,

C denotes a 1,3-allenylene, 1,1- or 1,2-vinylene group which may besubstituted in each case by one or two methyl groups or by atrifluoromethyl group,

an ethynylene group or

a 1,3-butadien-1,4-ylene group optionally substituted by 1 to 4 methylgroups or by a trifluoromethyl group,

D denotes an alkylene, —CO-alkylene or —SO₂-alkylene group wherein thealkylene moiety in each case contains 1 to 8 carbon atoms andadditionally 1 to 4 hydrogen atoms in the alkylene moiety may bereplaced by fluorine atoms, whilst the linking of the —CO-alkylene or—SO₂-alkylene group to the adjacent group C in each case must take placevia the carbonyl or sulfonyl group,

a —CO—O-alkylene, —CO—NR₄-alkylene or —SO₂—NR₄-alkylene group whereinthe alkylene moiety in each case contains 1 to 8 carbon atoms, whilstthe linking to the adjacent group C in each case must take place via thecarbonyl or sulfonyl group, wherein

-   -   R₄ denotes a hydrogen atom or a C₁₋₄-alkyl group,

or, if D is bound to a carbon atom of the group E, it may also denote abond

or, if D is bound to a nitrogen atom of the group E, it may also denotea carbonyl or sulfonyl group,

E denotes an amino, C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-amino groupwherein the alkyl moieties may be identical or different,

a C₂₋₄-alkylamino group wherein the alkyl moiety is substituted in β-,γ-, or δ-position with regard to the nitrogen atom of the amino group bythe group R₅, whilst

-   -   R₅ denotes a hydroxy, C₁₋₄-alkoxy, amino, C₁₋₄-alkylamino or        di-(C₁₋₄-alkyl)-amino group,    -   a 4- to 7-membered alkyleneimino group optionally substituted by        one or two methyl groups or    -   a 6- to 7-membered alkyleneimino group optionally substituted by        one or two methyl groups wherein in each case a methylene group        in position 4 is replaced by an oxygen or sulfur atom, by a        sulfinyl, sulfonyl, imino or N-(C₁₋₉₅ ₄-alkyl)-imino group,

an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein the C₂₋₄-alkylmoiety is substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, whilst R₅ is ashereinbefore defined,

a di-(C₂₋₄-alkyl)-amino group wherein the two C₂₋₄-alkyl moieties aresubstituted in each case in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, whilst thesubstituents may be identical or different and R₅ is as hereinbeforedefined,

a C₃₋₇-cycloalkylamino or C₃₋₇-cycloalkyl-C₁₋₃-alkylamino group whereinin each case the nitrogen atom may be substituted by a furtherC₁₋₄-alkyl group,

an amino or C₁₋₄-alkylamino group wherein in each case the nitrogen atomis substituted by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl,tetrahydropyran-4-yl, tetrahydrofuranylmethyl,1-(tetrahydrofuran-3-yl)piperidin-4-yl,1-(tetrahydropyran-3-yl)piperidin-4-yl,1-(tetrahydropyran-4-yl)piperidin-4-yl, 3-pyrrolidinyl, 3-piperidinyl,4-piperidinyl, 3-hexahydro-azepinyl or 4-hexahydro-azepinyl groupoptionally substituted by 1 to 3 C₁₋₄-alkyl groups,

a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4C₁₋₂-alkyl groups, which may be substituted by the group R₅ either at acyclic carbon atom or at one of the alkyl groups, whilst R₅ is ashereinbefore defined,

a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranylor tetrahydrofuranylmethyl group,

a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2C₁₋₂-alkyl groups wherein a methylene group in each case is replaced inthe 4 position by an oxygen or sulfur atom, by an imino groupsubstituted by the group R₆, or by a sulfinyl or sulfonyl group, whilst

-   -   R₆ denotes a hydrogen atom, a C₁₋₄-alkyl, 2-methoxyethyl,        3-methoxypropyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl,        tetrahydrofuran-3-yl, tetrahydropyran-3-yl,        tetrahydropyran-4-yl, tetrahydrofuranylmethyl, formyl,        C₁₋₄-alkylcarbonyl, C₁₋₄-alkylsulfonyl, aminocarbonyl,        C₁₋₄-alkylaminocarbonyl or di-(C₁₋₄-alkyl)-aminocarbonyl group,

an imidazolyl group optionally substituted by 1 to 3 methyl groups,

a C₅₋₇-cycloalkyl group wherein a methylene group is replaced by anoxygen or sulfur atom, by an imino group substituted by the group R₆, bya sulfinyl or sulfonyl group, whilst R₆ is as hereinbefore defined,

or D together with E denotes a hydrogen, fluorine or chlorine atom,

a C₁₋₄-alkyl group optionally substituted by 1 to 5 fluorine atoms,

a C₃₋₆-cycloalkyl group,

an aryl, heteroaryl, C₁₋₄-alkylcarbonyl or arylcarbonyl group,

a carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonylor di-(C₁₋₄-alkyl)-aminocarbonyl group or

a carbonyl which is substituted by a 4- to 7-membered alkyleneiminogroup, whilst in the abovementioned 6- to 7-membered alkyleneiminogroups in each case a methylene group may be replaced in the 4 positionby an oxygen or sulfur atom, by an imino group substituted by the groupR₆, by a sulfinyl or sulfonyl group, whilst R₆ is as hereinbeforedefined, and

R_(c) denotes a C₄₋₇-cycloalkoxy or C₃₋₇-cycloalkyl-C₁₋₆-alkoxy groupwherein the cycloalkyl moiety in each case may be substituted by aC₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy, amino, C₁₋₄-alkylamino,di-(C₁₋₄-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino,N-(C₁₋₂-alkyl)-piperazino, hydroxy-C₁₋₂-alkyl, C₁₋₄-alkoxy-C₁₋₂-alkyl,amino-C₁₋₂-alkyl, C₁₋₄-alkylamino-C₁₋₂-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₂-alkyl, pyrrolidino-C₁₋₂-alkyl,piperidino-C₁₋₂-alkyl, morpholino-C₁₋₂-alkyl, piperazino-C₁₋₂-alkyl orN-(C₁₋₂-alkyl)-piperazino-C₁₋₂-alkyl group, whilst the abovementionedmonosubstituted cycloalkyl moieties may additionally be substituted by aC₁₋₃-alkyl group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group,

an C₂₋₄-alkoxy group substituted in β-, γ-, or δ-position with regard tothe oxygen atom by an azetidin-1-yl, 4-methyl-homopiperazino or4-ethyl-homopiperazino group,

a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C₁₋₄-alkyloxy,3-pyrrolidinyl-C₁₋₄-alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy,2-piperidinyl-C₁₋₄-alkyloxy, 3-piperidinyl-C₁₋₄-alkyloxy,4-piperidinyl-C₁₋₄-alkyloxy, 3-hexahydro-azepinyloxy,4-hexahydro-azepinyloxy, 2-hexahydro-azepinyl-C₁₋₄-alkyloxy,3-Hexahydro-azepinyl-C₁₋₄-alkyloxy or 4-hexahydro-azepinyl-C₁₋₄-alkyloxygroup wherein in each case the cyclic nitrogen atom is substituted bythe group R₆, where R₆ is as hereinbefore defined,

particularly those compounds of general formula I wherein R_(a), R_(b),A to C and X are as hereinbefore defined,

E denotes an amino, C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-amino groupwherein the alkyl moieties may be identical or different,

a C₂₋₄-alkylamino group wherein the alkyl moiety is substituted fromposition 2 by the group R₅, whilst

-   -   R₅ denotes a hydroxy, C₁₋₄-alkoxy, amino, C₁₋₄-alkylamino or        di-(C₁₋₄-alkyl)-amino group,    -   a 4- to 7-membered alkyleneimino group optionally substituted by        one or two methyl groups or    -   a 6- to 7-membered alkyleneimino group optionally substituted by        one or two methyl groups wherein in each case a methylene group        in position 4 is replaced by an oxygen or sulfur atom, by a        sulfinyl, sulfonyl, imino or N-(C₁₋₄-alkyl)-imino group,

an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein the C₂₋₄-alkylmoiety is substituted from position 2 onwards by the group R₅, where R₅is as hereinbefore defined,

a di-(C₂₋₄-alkyl)-amino group wherein the two C₂₋₄-alkyl moieties aresubstituted in each case from position 2 onwards by the group R₅, whilstthe substituents may be identical or different and R₅ is as hereinbeforedefined,

a C₃₋₇-cycloalkylamino or C₃₋₇-cycloalkyl-C₁₋₃-alkylamino group whereinin each case the nitrogen atom may be substituted by a furtherC₁₋₄-alkyl group,

an amino or C₁₋₄-alkylamino group wherein in each case the nitrogen atomis substituted by a 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl,3-hexahydro-azepinyl or 4-hexahydro-azepinyl group optionallysubstituted by 1 to 3 C₁₋₄-alkyl groups,

a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4C₁₋₂-alkyl groups, which may be substituted by the group R₅ either at acyclic carbon atom or at one of the alkyl groups, whilst R₅ is ashereinbefore defined, or

a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2C₁₋₂-alkyl groups wherein a methylene group in each case is replaced inthe 4 position by an oxygen or sulfur atom, by an imino groupsubstituted by the group R₆, or by a sulfinyl or sulfonyl group, whilst

-   -   R₆ denotes a hydrogen atom, a C₁₋₄-alkyl, C₃₋₇-cycloalkyl,        C₃₋₇-cycloalkyl-C₁₋₄-alkyl, formyl, C₁₋₄-alkylcarbonyl,        C₁₋₄-alkylsulfonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonyl or        di-(C₁₋₄-alkyl)-aminocarbonyl group,

an imidazolyl group optionally substituted by 1 to 3 methyl groups,

a C₅₋₇-cycloalkyl group wherein a methylene group is replaced by anoxygen or sulfur atom, by an imino group substituted by the group R₆, bya sulfinyl or sulfonyl group, whilst R₆ is as hereinbefore defined,

or D together with E denotes a hydrogen, fluorine or chlorine atom,

a C₁₋₄-alkyl group optionally substituted by 1 to 5 fluorine atoms,

a C₃₋₆-cycloalkyl group,

an aryl, heteroaryl, C₁₋₄-alkylcarbonyl or arylcarbonyl group,

a carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonylor di-(C₁₋₄-alkyl)-aminocarbonyl group or

a carbonyl which is substituted by a 4- to 7-membered alkyleneiminogroup, whilst in the abovementioned 6- to 7-membered alkyleneiminogroups a methylene group may in each case be replaced in the 4 positionby an oxygen or sulfur atom, by an imino group substituted by the groupR₆, by a sulfinyl or sulfonyl group, whilst R₆ is as hereinbeforedefined, and

R_(c) denotes a C₄₋₇-cycloalkoxy or C₃₋₇-cycloalkyl-C₁₋₆-alkoxy groupwherein the cycloalkyl moiety in each case may be substituted by aC₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy, amino, C₁₋₄-alkylamino,di-(C₁₋₄-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino,N-(C₁₋₂-alkyl)-piperazino, hydroxy-C₁₋₂-alkyl, C₁₋₄-alkoxy-C₁₋₂-alkyl,amino-C₁₋₂-alkyl, C₁₋₄-alkylamino-C₁₋₂-alkyl,di-(C₁₋₄-alkyl)-amino-C₁₋₂-alkyl, pyrrolidino-C₁₋₂-alkyl,piperidino-C₁₋₂-alkyl, morpholino-C₁₋₂-alkyl, piperazino-C₁₋₂-alkyl orN-(C₁₋₂-alkyl)-piperazino-C₁₋₂-alkyl group, whilst the abovementionedmonosubstituted cycloalkyl moieties may additionally be substituted by aC₁₋₃-alkyl group, or

a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C₁₋₄-alkyloxy,3-pyrrolidinyl-C₁₋₄-alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy,2-piperidinyl-C₁₋₄-alkyloxy, 3-piperidinyl-C₁₋₄-alkyloxy,4-piperidinyl-C₁₋₄-alkyloxy, 3-hexahydro-azepinyloxy,4-hexahydro-azepinyloxy,

2-hexahydro-azepinyl-C₁₋₄-alkyloxy, 3-hexahydro-azepinyl-C₁₋₄-alkyloxyor 4-hexahydro-azepinyl-C₁₋₄-alkyloxy group wherein in each case thecyclic nitrogen atom is substituted by the group R₆, where R₆ is ashereinbefore defined.

By the aryl moieties mentioned in the definition of the abovementionedgroups is meant a phenyl group which in each case may be monosubstitutedby R₇, mono-, di- or trisubstituted by R₈ or monosubstituted by R₇ andadditionally mono- or disubstituted by R₈, wherein the substituents maybe identical or different and

-   -   R₇ denotes a cyano, carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl,        C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,        C₁₋₄-alkylsulfenyl, C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl,        hydroxy, C₁₋₄-alkylsulfonyloxy, trifluoromethyloxy, nitro,        amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        C₁₋₄-alkylcarbonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonylamino,        C₁₋₄-alkylsulfonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylsulfonylamino,        aminosulfonyl, C₁₋₄-alkylaminosulfonyl or        di-(C₁₋₄-alkyl)-aminosulfonyl group or a carbonyl group which is        substituted by a 5- to 7-membered alkyleneimino group, whilst in        the abovementioned 6- to 7-membered alkyleneimino groups in each        case a methylene group in the 4 position may be replaced by an        oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or        N-(C₁₋₄-alkyl)-imino group, and    -   R₈ denotes a fluorine, chlorine, bromine or iodine atom, a        C₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group or    -   two groups R₈, if they are bound to adjacent carbon atoms,        together denote a C₃₋₅-alkylene, methylenedioxy or        1,3-butadien-1,4-ylene group.

The heteroaryl groups mentioned in the definition of the abovementionedgroups also include a 5-membered heteroaromatic group which contains animino group, an oxygen or sulfur atom or an imino group, an oxygen orsulfur atom and one or two nitrogen atoms, or

a 6-membered heteroaromatic group which contains one, two or threenitrogen atoms, whilst the abovementioned 5-membered heteroaromaticgroups may be substituted in each case by 1 or 2 methyl or ethyl groupsand the abovementioned 6-membered heteroaromatic groups may besubstituted in each case by 1 or 2 methyl or ethyl groups or by afluorine, chlorine, bromine or iodine atom or by a trifluoromethyl,hydroxy, methoxy or ethoxy group.

Preferred compounds of the above general formula I are those wherein

R_(a) denotes a hydrogen atom,

R_(b) denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenylnucleus is substituted in each case by the groups R₁ to R₃, whilst

-   -   R₁ and R₂, which may be identical or different, in each case        denote a hydrogen, fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₃₋₆-cycloalkyl,        C₄₋₆-cycloalkoxy, C₂₋₅-alkenyl or C₂₋₅-alkynyl group,    -   an aryl, aryloxy, arylmethyl or arylmethoxy group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms,    -   a cyano or nitro group and    -   R₃ denotes a hydrogen, fluorine, chlorine or bromine atom,    -   a C₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group,

X denotes a methine group substituted by a cyano group or a nitrogenatom,

A denotes an imino group,

B denotes a carbonyl or sulfonyl group,

C denotes a 1,3-allenylene, 1,1- or 1,2-vinylene group,

an ethynylene or 1,3-butadien-1,4-ylene group,

D denotes an alkylene, —CO-alkylene or —SO₂-alkylene group wherein thealkylene moiety in each case contains 1 to 4 carbon atoms andadditionally 1 to 4 hydrogen atoms in the alkylene moiety may bereplaced by fluorine atoms, whilst the linking of the —CO-alkylene or—SO₂-alkylene group to the adjacent group C in each case must take placevia the carbonyl or sulfonyl group,

a —CO—O-alkylene, —CO—NR₄-alkylene or —SO₂—NR₄-alkylene group whereinthe alkylene moiety in each case contains 1 to 4 carbon atoms, whilstthe linking to the adjacent group C in each case must take place via thecarbonyl or sulfonyl group, wherein

-   -   R₄ denotes a hydrogen atom or a C₁₋₄-alkyl group,

or, if D is bound to a carbon atom of the group E, it may also denote abond,

or, if D is bound to a nitrogen atom of the group E, it may also denotea carbonyl or sulfonyl group,

E denotes a di-(C₁₋₄-alkyl)-amino group wherein the alkyl moieties maybe identical or different,

an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein the C₂₋₄-alkylmoiety is substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, where

-   -   R₅ denotes a hydroxy, C₁₋₄-alkoxy or di-(C₁₋₄-alkyl)-amino        group,    -   a 4- to 7-membered alkyleneimino group optionally substituted by        one or two methyl groups or    -   a 6- to 7-membered alkyleneimino group optionally substituted by        one or two methyl groups wherein in each case a methylene group        in position 4 is replaced by an oxygen or sulfur atom, or by a        sulfinyl, sulfonyl or N-(C₁₋₄-alkyl)-imino group,

a di-(C₂₋₄-alkyl)-amino group wherein the two C₂₋₄-alkyl moieties ineach case are substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, wherein thesubstituents may be identical or different and R₅ is as hereinbeforedefined,

a C₃₋₇-cycloalkylamino or C₃₋₇-cycloalkyl-C₁₋₃-alkylamino group whereinin each case the nitrogen atom is substituted by a further C₁₋₄-alkylgroup,

a C₁₋₄-alkylamino group wherein the nitrogen atom is substituted by atetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,tetrahydrofuranylmethyl, 1-(tetrahydrofuran-3-yl)piperidin-4-yl,1-(tetrahydropyran-3-yl)piperidin-4-yl,1-(tetrahydropyran-4-yl)piperidin-4-yl, N-(C₁₋₂-alkyl)-3-pyrrolidinyl,N-(C₁₋₂-alkyl)-3-piperidinyl, N-(C₁₋₂-alkyl)-4-piperidinyl,N-(C₁₋₂-alkyl)-3-hexahydro-azepinyl orN-(C₁₋₂-alkyl)-4-hexahydro-azepinyl group,

an 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4methyl groups, which may be substituted either at a cyclic carbon atomor at one of the methyl groups by the group R₅, where R₅ is ashereinbefore defined,

a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranylor tetrahydrofuranylmethyl group,

a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2methyl groups wherein in each case a methylene group is replaced in the4 position by an oxygen or sulfur atom, by an imino group substituted bythe group R₆, by a sulfinyl or sulfonyl group, whilst

-   -   R₆ denotes a C₁₋₄-alkyl, 2-methoxyethyl, 3-methoxypropyl,        C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl,        tetrahydrofuran-3-yl, tetrahydropyran-3-yl,        tetrahydropyran-4-yl, tetrahydrofuranylmethyl, formyl,        C₁₋₄-alkylcarbonyl, C₁₋₄-alkylsulfonyl, aminocarbonyl,        C₁₋₄-alkylaminocarbonyl or di-(C₁₋₄-alkyl)-aminocarbonyl group,

a C₅₋₇-cycloalkyl group wherein a methylene group is replaced by anoxygen or sulfur atom, by an imino group substituted by the group R₆, orby a sulfinyl or sulfonyl group, where R₆ is as hereinbefore defined,

or D together with E denotes a hydrogen, fluorine or chlorine atom,

a C₁₋₄-alkyl group optionally substituted by 1 to 5 fluorine atoms,

a C₃₋₆-cycloalkyl group,

an aryl, C₁₋₄-alkylcarbonyl or arylcarbonyl group,

a carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonylor di-(C₁₋₄-alkyl)-aminocarbonyl group or

a carbonyl group which is substituted by a 4- to 7-memberedalkyleneimino group, whilst in the abovementioned 6- to 7-memberedalkyleneimino groups in each case a methylene group in the 4 positionmay be replaced by an oxygen or sulfur atom, by an imino groupsubstituted by the group R₆, or by a sulfinyl or sulfonyl group, whereR₆ is as hereinbefore defined, and

R_(c) denotes a C₄₋₇-cycloalkoxy or C₃₋₇-cycloalkyl-C₁₋₆-alkoxy groupwherein the cycloalkyl moiety in each case may be substituted by aC₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy, di-(C₁₋₄-alkyl)-amino, pyrrolidino,piperidino, morpholino, N-(C₁₋₂-alkyl)-piperazino, hydroxy-C₁₋₂-alkyl,C₁₋₄-alkoxy-C₁₋₂-alkyl, di-(C₁₋₄-alkyl)-amino-C₁₋₂-alkyl,pyrrolidino-C₁₋₂-alkyl, piperidino-C₁₋₂-alkyl, morpholino-C₁₋₂-alkyl orN-(C₁₋₂-alkyl)-piperazino-C₁₋₂-alkyl group, whilst the abovementionedmonosubstituted cycloalkyl moieties may additionally be substituted by aC₁₋₃-alkyl group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group,

an C₂₋₄-alkoxy group substituted in β-, γ-, or δ-position with regard tothe oxygen atom by an azetidin-1-yl, 4-methyl-homopiperazino or4-ethyl-homopiperazino group,

a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C₁₋₄-alkyloxy,3-pyrrolidinyl-C₁₋₄-alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy,2-piperidinyl-C₁₋₄-alkyloxy, 3-piperidinyl-C₁₋₄-alkyloxy,4-piperidinyl-C₁₋₄-alkyloxy, 3-hexahydro-azepinyloxy,4-hexahydro-azepinyloxy, 2-hexahydro-azepinyl-C₁₋₄-alkyloxy,3-hexahydro-azepinyl-C₁₋₄-alkyloxy or 4-hexahydro-azepinyl-C₁₋₄-alkyloxygroup wherein in each case the cyclic nitrogen atom is substituted bythe group R₆, where R₆ is as hereinbefore defined, whilst

by the aryl moieties mentioned in the definition of the abovementionedgroups is meant a phenyl group which may in each case be monosubstitutedby R₇, mono-, di- or trisubstituted by R₈ or monosubstituted by R₇ andadditionally mono- or disubstituted by R₈, wherein the substituents maybe identical or different and

-   -   R₇ denotes a cyano, carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl,        C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,        C₁₋₄-alkylsulfenyl, C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl,        hydroxy, C₁₋₄-alkylsulfonyloxy, trifluoromethyloxy, nitro,        amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,        C₁₋₄-alkylcarbonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonylamino,        C₁₋₄-alkylsulfonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylsulfonylamino,        aminosulfonyl, C₁₋₄-alkylaminosulfonyl or        di-(C₁₋₄-alkyl)-aminosulfonyl group or a carbonyl group which is        substituted by a 5- to 7-membered alkyleneimino group, whilst in        the abovementioned 6- to 7-membered alkyleneimino groups in each        case a methylene group may be replaced in the 4 position by an        oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or        N-(C₁₋₄-alkyl)-imino group, and    -   R₈ denotes a fluorine, chlorine, bromine or iodine atom, a        C₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group or    -   two groups R₈, if they are bound to adjacent carbon atoms,        together denote a C₃₋₅-alkylene, methylenedioxy or        1,3-butadien-1,4-ylene group,

the tautomers, stereoisomers and salts thereof.

Particularly preferred compounds of the above general formula I arethose wherein

R_(a) denotes a hydrogen atom,

R_(b) denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenylnucleus is substituted in each case by the groups R₁ and R₂, where

-   -   R₁ and R₂, which may be identical or different, in each case        denote a hydrogen, fluorine, chlorine or bromine atom,    -   a methyl, trifluoromethyl or methoxy group,

X denotes a nitrogen atom,

A denotes an imino group,

B denotes a carbonyl group,

C denotes a 1,2-vinylene group,

an ethynylene or 1,3-butadien-1,4-ylene group,

D denotes a C₁₋₄-alkylene group,

or, if D is bound to a carbon atom of the group E, it may also denote abond,

or, if D is bound to a nitrogen atom of the group E, it may also denotea carbonyl group,

E denotes a di-(C₁₋₄-alkyl)-amino group wherein the alkyl moieties maybe identical or different,

an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein the C₂₋₄-alkylmoiety is substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, whilst

-   -   R₅ denotes a hydroxy, C₁₋₃-alkoxy or di-(C₁₋₃-alkyl)-amino        group,    -   a pyrrolidino, piperidino or morpholino group,

a di-(C₂₋₄-alkyl)-amino group wherein the two C₂₋₄-alkyl moieties ineach case are substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, wherein thesubstituents may be identical or different and R₅ is as hereinbeforedefined,

an C₁₋₄-alkylamino group substituted at the nitrogen atom by atetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,tetrahydrofuranylmethyl, 1-(C₁₋₂-alkyl)-pyrrolidin-3-yl,1-(C₁₋₂-alkyl)-piperidin-3-yl, 1-(C₁₋₂-alkyl)-piperidin-4-yl,1-(tetrahydrofuran-3-yl)piperidin-4-yl,1-(tetrahydropyran-3-yl)piperidin-4-yl or1-(tetrahydropyran-4-yl)piperidin-4-yl group,

a C₃₋₅-cycloalkylamino or C₃₋₅-cycloalkyl-C₁₋₃-alkylamino group whereinin each case the nitrogen atom is substituted by a further C₁₋₃-alkylgroup,

a 5- to 7-membered alkyleneimino group optionally substituted by 1 or 2methyl groups which may be substituted either at a cyclic carbon atom orat one or the methyl groups by the group R₅, where R₅ is as hereinbeforedefined, or

a piperidino group substituted by a tetrahydrofuranyl, tetrahydropyranylor tetrahydrofuranylmethyl group,

a piperidino group optionally substituted by 1 or 2 methyl groupswherein the methylene group is replaced in the 4 position by an oxygenor sulfur atom, by sulfinyl or sulfonyl group or by an imino groupsubstituted by the group R₆, whilst

-   -   R₆ denotes a C₁₋₃-alkyl, 2-methoxyethyl, 3-methoxypropyl,        C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl,        tetrahydrofuran-3-yl, tetrahydropyran-3-yl,        tetrahydropyran-4-yl, tetrahydrofuranylmethyl,        C₁₋₃-alkylcarbonyl, C₁₋₃-alkylsulfonyl, aminocarbonyl,        C₁₋₃-alkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group,

or D together with E denotes a hydrogen atom,

a C₁₋₃-alkyl group,

an aryl or C₁₋₄-alkylcarbonyl group or

a C₁₋₄-alkoxycarbonyl group,

R_(c) denotes a C₄₋₇-cycloalkoxy or C₃₋₇-cycloalkyl-C₁₋₄-alkoxy groupwherein the cycloalkyl moiety in each case may be substituted by aC₁₋₃-alkyl or C₁₋₃-alkoxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy,tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group,

an C₂₋₄-alkoxy group substituted in β-, γ-, or δ-position with regard tothe oxygen atom by an azetidin-1-yl, 4-methyl-homopiperazino or4-ethyl-homopiperazino group,

a 3-pyrrolidinyloxy, 2-pyrrolidinyl-C₁₋₃-alkyloxy,3-pyrrolidinyl-C₁₋₃-alkyloxy, 3-piperidinyloxy, 4-piperidinyloxy,2-piperidinyl-C₁₋₃-alkyloxy, 3-piperidinyl-C₁₋₃-alkyloxy,4-piperidinyl-C₁₋₃-alkyloxy, 3-hexahydro-azepinyloxy,4-hexahydro-azepinyloxy, 2-hexahydro-azepinyl-C₁₋₃-alkyloxy,3-hexahydro-azepinyl-C₁₋₃-alkyloxy or 4-hexahydro-azepinyl-C₁₋₃-alkyloxygroup wherein in each case the cyclic nitrogen atom is substituted by amethyl or ethyl group, whilst

by the aryl moieties mentioned in the definition of the abovementionedgroups is meant a phenyl group which may be mono-, di- or trisubstitutedby R₈, wherein the substituents may be identical or different and

-   -   R₈ denotes a fluorine, chlorine, bromine or iodine atom, a        C₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group,

the tautomers, stereoisomers and salts thereof.

Most particularly preferred compounds of the above general formula I arethose wherein

R_(a) denotes a hydrogen atom,

R_(b) denotes a phenyl, benzyl or 1-phenylethyl group, whilst the phenylnucleus is substituted in each case by the radicals R₁ and R₂, whilst

-   -   R₁ and R₂, which may be identical or different, each denotes a        hydrogen, fluorine, chlorine or bromine atom,

X denotes a nitrogen atom,

A denotes an imino group,

B denotes a carbonyl group,

C denotes a 1,2-vinylene, ethinylene or 1,3-butadien-1,4-ylene group,

D denotes an C₁₋₃-alkylene group,

E denotes a Di-(C₁₋₄-alkyl)-amino group, wherein the alkyl moieties maybe identical or different,

a methylamino or ethylamino group each substituted at the nitrogen atomby a 2-methoxyethyl, 1-methoxy-2-propyl, 2-methoxypropyl,3-methoxypropyl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl,tetrahydrofuran-2-ylmethyl, 1-methylpiperidin-4-yl,1-ethylpiperidin-4-yl, 1-(tetrahydrofuran-3-yl)piperidin-4-yl,cyclopropyl or cyclopropylmethyl group,

a Bis-(2-methoxyethyl)amino group,

a pyrrolidino, piperidino or morpholino group each optionallysubstituted by one or two methyl groups,

a piperazino group substituted in 4-position by a methyl, ethyl,cyclopropyl, cyclopropylmethyl, 2-methoxyethyl, tetrahydrofuran-3-yl,tetrahydropyran-4-yl or tetrahydrofuran-2-ylmethyl group,

a thiomorpholino, S-oxidothiomorpholino or S,S-dioxidothiomorpholinogroup,

a 2-(methoxymethyl)pyrrolidino, 2-(ethoxymethyl)pyrrolidino,4-hydroxypiperidino, 4-methoxypiperidino, 4-ethoxypiperidino,4-(tetrahydrofuran-3-yl)piperidino or 4-morpholinopiperidino group

or D together with E denote a hydrogen atom, a methyl, phenyl,methoxycarbonyl or ethoxycarbonyl group and

R_(c) denotes a cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy or cyclohexylmethoxy group,

a cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group,

a tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy ortetrahydrofuran-2-ylmethoxy group,

a straight chained C₂₋₄-alkoxy group terminally substituted by anazetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino group,

a 1-methylpiperidin-4-yloxy or 1-ethylpiperidin-4-yloxy group,

a (1-methylpiperidin-4-yl)-C₁₋₃-alkyloxy or(1-ethylpiperidin-4-yl)-C₁₋₃-alkyloxy group,

especially those compounds wherein

R_(a) denotes a hydrogen atom,

R_(b) denotes a 1-phenylethyl group or a phenyl group wherein the phenylnucleus is substituted by the radicals R₁ and R₂, whilst

-   -   R₁ and R₂, which may be identical or different, each denote a        hydrogen, fluorine, chlorine or bromine atom,

X denotes a nitrogen atom,

A denotes an imino group,

B denotes a carbonyl group,

C denotes a 1,2-vinylene, ethinylene or 1,3-butadien-1,4-ylene group,

D denotes a methylene group,

E denotes a dimethylamino, diethylamino, bis(2-methoxyethyl)amino,N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,N-methyl-N-cyclopropyl-amino, N-methyl-N-cyclopropylmethyl-amino,N-methyl-N-(1-methoxy-2-propyl)amino, N-methyl-N-(2-methoxypropyl)amino,N-methyl-N-(3-methoxypropyl)amino-,N-methyl-N-(tetrahydrofuran-3-yl)amino,N-methyl-N-(tetrahydropyran-4-yl)amino,N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino orN-methyl-N-(1-methylpiperidin-4-yl)amino group,

a pyrrolidino, piperidino or morpholino group each optionallysubstituted by one or two methyl groups,

a piperazino group substituted in 4-position by a methyl, ethyl,cyclopropylmethyl or 2-methoxyethyl group,

a S-oxidothiomorpholino group,

a 2-(methoxymethyl)pyrrolidino, 4-hydroxypiperidino or4-methoxypiperidino group

or D together with E denote a hydrogen atom, a methyl, phenyl orethoxycarbonyl group, and

R_(c) denotes a cyclopropylmethoxy, cyclobutyloxy or cyclopentyloxygroup,

a tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy ortetrahydrofuran-2-ylmethoxy group,

a straight chained C₂₋₄-alkoxy group terminally substituted by anazetidin-1-yl or 4-methyl-homopiperazino group,

a 1-methylpiperidin-4-yloxy group or

a (1-methylpiperidin-4-yl)-C₁₋₃-alkyloxy group,

the tautomers, stereoisomers and salts thereof.

The following particularly valuable compounds of general formula I maybe mentioned by way of example:

-   (a)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline,-   (b)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline    and-   (c)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline    as well as the salts thereof.

The compounds of general formula I may be prepared, for example, by thefollowing processes:

-   a) reacting a compound of general formula

R_(a) to R_(c), A and X are as hereinbefore defined, with a compound ofgeneral formulaZ₁-B-C-D-E  (III)wherein

B to E are as hereinbefore defined and

Z₁ denotes a leaving group such as a halogen atom, e.g., a chlorine orbromine atom, or a hydroxy group.

The reaction is optionally carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide, benzene,toluene, chlorobenzene, tetrahydrofuran, benzene/-tetrahydrofuran ordioxane optionally in the presence of an inorganic or organic base andoptionally in the presence of a dehydrating agent, expediently attemperatures between −50° C. and 150° C., preferably at temperaturesbetween −20° C. and 80° C.

With a compound of general formula III wherein Z₁ denotes a leavinggroup, the reaction is optionally carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide, benzene,toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran ordioxane conveniently in the presence of a tertiary organic base such astriethylamine, pyridine or 2-dimethylaminopyridine, in the presence ofN-ethyl-diisopropylamine (Hünig base), whilst these organic bases maysimultaneously also act as solvent, or in the presence of an inorganicbase such as sodium carbonate, potassium carbonate or sodium hydroxidesolution expediently at temperatures between −50° C. and 150° C.,preferably at temperatures between −20° C. and 80° C.

With a compound of general formula III wherein Z₁ denotes a hydroxygroup, the reaction is preferably carried out in the presence of adehydrating agent, e.g., in the presence of isobutyl chloroformate,thionyl chloride, trimethyl chlorosilane, phosphorus trichloride,phosphorus pentoxide, hexamethyldisilazane,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole and optionally also in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, expediently in a solvent suchas methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene,dimethylsulfoxide, ethylene glycol monomethylether, ethylene glycol,diethylether or sulfolane and optionally in the presence of a reactionaccelerator such as 4-dimethylaminopyridine at temperatures between −50°C. and 150° C., but preferably at temperatures between −20° C. and 80°C.

-   b) In order to prepare compounds of general formula I wherein the    group E is linked to the group D via a nitrogen atom:

reacting a compound of general formula

R_(a) to R_(c), A to D and X are as hereinbefore defined and Z₂

denotes a leaving group such as a halogen atom, a substituted hydroxy orsulfonyloxy group such as a chlorine or bromine atom, amethanesulfonyloxy or p-toluenesulfonyloxy group, with a compound ofgeneral formulaH-E′  (V)wherein

E′ denotes one of the groups mentioned for E hereinbefore, which islinked to the group D via a nitrogen atom.

The reaction is expediently carried out in a solvent such asisopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene,dimethylformamide, dimethylsulfoxide, methylene chloride, ethyleneglycol monomethylether, ethylene glycol diethylether or sulfolane,optionally in the presence of an inorganic or tertiary organic base,e.g., sodium carbonate or potassium hydroxide, a tertiary organic base,e.g., triethylamine, or in the presence of N-ethyl-diisopropylamine(Hünig base), whilst these organic bases may simultaneously also serveas solvent, and optionally in the presence of a reaction acceleratorsuch as an alkali metal halide at temperatures between −20° C. and 150°C., but preferably at temperatures between −10° C. and 100° C. Thereaction may, however, also be carried out without a solvent or in anexcess of the compound of general formula V used.

If according to the invention a compound of general formula I isobtained which contains an amino, alkylamino or imino group, this may beconverted by acylation or sulfonylation into a corresponding acyl orsulfonyl compound of general formula I or

if a compound of general formula I is obtained which contains an amino,alkylamino or imino group, this may be converted by alkylation orreductive alkylation into a corresponding alkyl compound of generalformula I or

if a compound of general formula I is obtained which contains a carboxyor hydroxyphosphoryl group, this may be converted by esterification intoa corresponding ester of general formula I or

if a compound of general formula I is obtained which contains a carboxyor ester group, this may be converted by reaction with an amine into acorresponding amide of general formula I.

The subsequent esterification is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane or most advantageously in acorresponding alcohol, optionally in the presence of an acid such ashydrochloric acid or in the presence of a dehydrating agent, e.g., inthe presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, sulfuric acid, methanesulfonic acid,p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole and optionally additionally in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0° C. and 150° C., preferably at temperatures between 0° C. and80° C.

The subsequent ester formation may also be carried out by reacting acompound which contains a carboxy or hydroxyphosphoryl group with acorresponding alkyl halide.

The subsequent acylation or sulfonylation is conveniently carried out ina solvent or mixture of solvents such as methylene chloride,dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane with a corresponding acyl or sulfonylderivative optionally in the presence of a tertiary organic base or inthe presence of an inorganic base or in the presence of a dehydratingagent, e.g., in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid,p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole and optionally also in the presence of4-dimethylamino-pyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, expediently at temperaturesbetween 0° C. and 150° C., preferably at temperatures between 0° C. and80° C.

The subsequent alkylation is optionally carried out in a solvent ormixture of solvents such as methylene chloride, dimethylformamide,benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane with an alkylating agent such as acorresponding halide or sulfonic acid ester, e.g., with methyl iodide,ethyl bromide, dimethyl sulfate or benzyl chloride, optionally in thepresence of a tertiary organic base or in the presence of an inorganicbase, expediently at temperatures between 0° C. and 150° C., preferablyat temperatures between 0° C. and 100° C.

The subsequent reductive alkylation is carried out with a correspondingcarbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde,acetone or butyraldehyde in the presence of a complex metal hydride suchas sodium borohydride, lithium borohydride, sodium triacetoxyborohydrideor sodium cyanoborohydride, expediently at a pH of 6–7 and at ambienttemperature or in the presence of a hydration catalyst, e.g., withhydrogen in the presence of palladium/charcoal, at a hydrogen pressureof 1 to 5 bar. The methylation can also be carried out in the presenceof formic acid as reduction agent at elevated temperatures, e.g., attemperatures between 60° C. and 120° C.

The subsequent amide formation is carried out by reacting acorresponding reactive carboxylic acid derivative with a correspondingamine, optionally in a solvent or mixture of solvents such as methylenechloride, dimethylformamide, benzene, toluene, chlorobenzene,tetrahydrofuran, benzene/tetrahydrofuran or dioxane, whilst the amineused may simultaneously serve as solvent, optionally in the presence ofa tertiary organic base or in the presence of an inorganic base or witha corresponding carboxylic acid in the presence of a dehydrating agent,e.g., in the presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxybenzotriazole and optionally also in the presence of4-dimethylaminopyridine, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, expediently at temperaturesbetween 0° C. and 150° C., preferably at temperatures between 0 and 80°C.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, carboxy, phosphono, O-alkyl-phosphono, amino,alkylamino or imino groups may be protected during the reaction byconventional protecting groups which are cleaved again after thereaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl,benzyl or tetrahydropyranyl group,

protecting groups for a carboxy group may be a trimethylsilyl, methyl,ethyl, tert-butyl, benzyl or tetrahydropyranyl group,

protecting groups for a phosphono group may be an alkyl group such asthe methyl, ethyl, isopropyl or n-butyl group, the phenyl or benzylgroup, and

protecting groups for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulfuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g., in the presenceof iodotrimethylsilane, at temperatures between 0° C. and 120° C.,preferably at temperatures between 10° C. and 100° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example hydrogenolytically, e.g., with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0° C. and 100° C., but preferably at temperatures between 20° C.and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxane, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50° C. and 120° C. or by treatingwith sodium hydroxide solution optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0° C. and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20° C. and 50° C.

A single alkyl group may be cleaved from an O,O′-dialkylphosphono groupwith sodium iodide, for example, in a solvent such as acetone, methylethyl ketone, acetonitrile or dimethylformamide at temperatures between40° C. and 150° C., but preferably at temperatures between 60° C. and100° C.

Both alkyl groups may be cleaved from an O,O′-dialkylphosphono groupwith iodotrimethylsilane, bromotrimethylsilane orchlorotrimethylsilane/sodium iodide, for example, in a solvent such asmethyl chloride, chloroform or acetonitrile at temperatures between 0°C. and the boiling temperature of the reaction mixture, but preferablyat temperatures between 20° C. and 60° C.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cisltrans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. N. L. Allinger and E. L. Eliel in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g., bychromatography and/or fractional crystallization, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g., esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g., on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g., the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.An optically active alcohol may be for example (+) or (−)-menthol and anoptically active acyl group in amides, for example, may be a (+)-or(−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I thus obtained contain acarboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group, they maysubsequently, if desired, be converted into the salts thereof withinorganic or organic bases, particularly for pharmaceutical use into thephysiologically acceptable salts thereof. Suitable bases for thispurpose include for example sodium hydroxide, potassium hydroxide,arginine, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The compounds of general formulae II to V used as starting materials areknown from the literature in some cases or may be obtained by methodsknown from the literature (cf. Examples I to VII).

For example, a starting compound of general formula I is obtained byreacting a 7-fluoro-6-nitro compound correspondingly substituted in the4 position with a corresponding alkoxide and subsequently reducing thenitro compound thus obtained or

a starting compound of general formula IV is obtained by reacting a7-fluoro-6-nitro compound correspondingly substituted in the 4 positionwith a corresponding alkoxide, subsequently reducing the nitro compoundthus obtained and then acylating with a corresponding compound.

As already mentioned hereinbefore, the compounds of general formula Iaccording to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on signal transduction mediated by the EpidermalGrowth Factor receptor (EGF-R), whilst this may be achieved for exampleby inhibiting ligand bonding, receptor dimerization or tyrosine kinaseitself. It is also possible to block the transmission of signals tocomponents located further down.

The biological properties of the new compounds were investigated asfollows:

The inhibition of the EGF-R-mediated signal transmission can bedemonstrated e.g., with cells which express human EGF-R and whosesurvival and proliferation depend on stimulation by EGF or TGF-alpha. Acell line of murine origin dependent on interleukin-3-(IL-3) which wasgenetically modified to express functional human EGF-R was used here.The proliferation of these cells known as F/L-HERc can therefore bestimulated either by murine IL-3 or by EGF (cf. T. von Rüden et al.,EMBO J. 7, 2749–2756 (1988) and J. H Pierce et al., Science 239, 628–631(1988)).

The starting material used for the F/L-HERc cells was the cell lineFDC-P₁, the production of which has been described by T. M. Dexter etal., J. Exp. Med. 152, 1036–1047 (1980). Alternatively, however, othergrowth-factor-dependent cells may also be used (cf., for example, J. H.Pierce et al., Science 239, 628–631 (1988); H. Shibuya et al., Cell 70,57–67 (1992); and W. S. Alexander et al., EMBO J. 10, 3683–3691 (1991)).For expressing the human EGF-R cDNA (cf. Ullrich, A. et al. in Nature309, 418–425 (1984)) recombinant retroviruses were used as described byT. von Rüden et al., EMBO J. 7, 2749–2756 (1988), except that theretroviral vector LXSN (cf. A. D. Miller et al., BioTechniques 7,980–990 (1989)) was used for the expression of the EGF-R cDNA and theline GP+E86 (cf. D. Markowitz et al., J. Virol. 62, 1120–1124 (1988))was used as the packaging cell.

The test was performed as follows:

F/L-HERc cells were cultivated in RPMI/1640 medium (BioWhittaker),supplemented with 10% fetal calf serum (FCS, Boehringer Mannheim), 2 mMglutamine (BioWhittaker), standard antibiotics and 20 ng/ml of human EGF(Promega), at 37° C. and 5% CO₂. In order to investigate the inhibitoryactivity of the compounds according to the invention, 1.5×10⁴ cells perwell were cultivated in triplicate in 96-well dishes in the above medium(200 μl), the cell proliferation being stimulated with either EGF (20ng/ml) or murine IL-3. The IL-3 used was obtained from culturesupernatants of the cell line X63/0 mIL-3 (cf. H. Karasuyama et al.,Eur. J. Immunol. 18, 97–104 (1988)). The compounds according to theinvention were dissolved in 100% dimethylsulfoxide (DMSO) and added tothe cultures in various dilutions, the maximum DMSO concentration being1%. The cultures were incubated for 48 hours at 37° C.

In order to determine the inhibitory activity of the compounds accordingto the invention the relative cell number was measured in O.D. unitsusing the Cell Titer 96™ Aqueous Non-Radioactive Cell ProliferationAssay (Promega). The relative cell number was calculated as a percentageof the control (F/LHERc cells without inhibitor) and the concentrationof active substance which inhibits the proliferation of the cells by 50%(IC₅₀) was derived therefrom.

The following results were obtained:

Compound Inhibition of EGF-Dependent Proliferation (Example No.) IC₅₀[nM] 1 <0.35 2(3) 0.35 1(7) <0.5 3 5 3(1) 0.2

The compounds of general formula I according to the invention thusinhibit signal transduction by tyrosine kinases, as demonstrated by theexample of the human EGF receptor, and are therefore useful for treatingpathophysiological processes caused by hyperfunction of tyrosinekinases. These are e.g., benign or malignant tumors, particularly tumorsof epithelial and neuroepithelial origin, metastasization and theabnormal proliferation of vascular endothelial cells (neoangiogenesis).

The compounds according to the invention are also useful for preventingand treating diseases of the airways and lungs which are accompanied byincreased or altered production of mucus caused by stimulation bytyrosine kinases, e.g., in inflammatory diseases of the airways such aschronic bronchitis, chronic obstructive bronchitis, asthma,bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cysticfibrosis, α₁-antitrypsin deficiency, or coughs, pulmonary emphysema,pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for treating diseases of thegastrointestinal tract and bile duct and gall bladder which areassociated with disrupted activity of the tyrosine kinases, such as maybe found e.g., in chronic inflammatory changes such as cholecystitis,Crohns' disease, ulcerative colitis, and ulcers in the gastrointestinaltract or such as may occur in diseases of the gastrointestinal tractwhich are associated with increased secretions, such as Ménétrier'sdisease, secreting adenomas and protein loss syndrome.

In addition, the compounds of general formula I and the physiologicallyacceptable salts thereof may be used to treat other diseases caused byabnormal function of tyrosine kinases, such as e.g., epidermalhyperproliferation (psoriasis), inflammatory processes, diseases of theimmune system, hyperproliferation of hematopoietic cells, etc.

By reason of their biological properties the compounds according to theinvention may be used on their own or in conjunction with otherpharmacologically active compounds, for example in tumour therapy, inmonotherapy or in conjunction with other anti-tumour therapeutic agents,for example in combination with topoisomerase inhibitors (e.g.,etoposide), mitosis inhibitors (e.g., vinblastine), compounds whichinteract with nucleic acids (e.g., cis-platin, cyclophosphamide,adriamycin), hormone antagonists (e.g., tamoxifen), inhibitors ofmetabolic processes (e.g., 5-FU etc.), cytokines (e.g., interferons),antibodies, etc. For treating respiratory tract diseases, thesecompounds may be used on their own or in conjunction with othertherapeutic agents for the airways, such as substances with asecretolytic, broncholytic and/or antiinflammatory activity. Fortreating diseases in the region of the gastrointestinal tract, thesecompounds may also be administered on their own or in conjunction withsubstances having an effect on motility or secretion. These combinationsmay be administered either simultaneously or sequentially.

These compounds may be administered either on their own or inconjunction with other active substances by intravenous, subcutaneous,intramuscular, intraperitoneal or intranasal route, by inhalation ortransdermally or orally, whilst aerosol formulations are particularlysuitable for inhalation.

For pharmaceutical use the compounds according to the invention aregenerally used for warm-blooded vertebrates, particularly humans, indoses of 0.01–100 mg/kg of body weight, preferably 0.1–15 mg/kg. Foradministration they are formulated with one or more conventional inertcarriers and/or diluents, e.g., with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat orsuitable mixtures thereof in conventional galenic preparations such asplain or coated tablets, capsules, powders, suspensions, solutions,sprays or suppositories.

The following Examples are intended to illustrate the present inventionwithout restricting it:

Preparation of the starting compounds:

EXAMPLE I6-Amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline

1.00 g of4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroquinazolineis dissolved in 16 ml of water, 35 ml of ethanol and 1.3 ml of glacialacetic acid and heated to boiling. Then 540 mg of iron powder are addedwith stirring. The reaction mixture is refluxed for about another 35minutes. For working up the cooled reaction mixture is diluted with 15ml of ethanol, made alkaline with 15 N sodium hydroxide solution,combined with 20 g of Extrelute and stirred for about 20 minutes. Theprecipitate formed is suction filtered and washed with 200 ml of warmethanol. The filtrate is concentrated by evaporation, mixed with about30 ml of water and extracted 3× with 70 ml of methylenechloride/methanol (9:1) each time. The combined extracts are dried oversodium sulfate and concentrated by evaporation, leaving a beige solid.Yield: 716 mg (76% of theory); melting point: 191° C.–198° C.; massspectrum (ESI⁺): m/z=470, 472 [M+H]⁺.

The following compounds are obtained analogously to Example I:

-   (1)    6-Amino-4-[(3-bromophenyl)amino]-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinazoline

Melting point: 197° C.; mass spectrum (ESI⁺): m/z=456, 458 [M+H]⁺.

-   (2)    6-Amino-4-[(3-bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline

Melting point: 207° C.–208° C.; mass spectrum (ESI⁺): m/z=442, 444[M+H]⁺.

-   (3)    6-Amino-4-[(3-bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]quinazoline

Melting point: 170° C.; mass spectrum (ESI⁺): m/z=428, 430 [M+H]⁺.

-   (4)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazoline

Melting point: 209° C.; R_(f) value: 0.68 (silica gel, ethyl acetate).

-   (5)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclobutyloxyquinazoline

R_(f) value: 0.32 (silica gel, cyclohexane/ethyl acetate=3:4); massspectrum (ESI⁺): m/z=359, 361 [M+H]⁺.

-   (6)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopentyloxyquinazoline

R_(f) value: 0.33 (silica gel, cyclohexane/ethyl acetate=1:1); massspectrum (ESI⁺): m/z=373, 375 [M+H]⁺.

-   (7) 6-Amino-4-[(R)-(1-phenylethyl)amino]-7-cyclobutyloxyquinazoline

R_(f) value: 0.28 (silica gel, ethyl acetate); mass spectrum (ESI⁺):m/z=335 [M+H]⁺.

-   (8)    6-Amino-4-[(R)-(1-phenylethyl)amino]-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.54 (silica gel, ethyl acetate); mass spectrum (ESI⁺):m/z=335 [M+H]⁺.

-   (9) 6-Amino-4-[(R)-(1-phenylethyl)amino]-7-cyclopentyloxyquinazoline

R_(f) value: 0.20 (silica gel, ethyl acetate); mass spectrum (ESI⁺):m/z=349 [M+H]⁺.

-   (10)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline

R_(f) value: 0.12 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=444, 446[M+H]⁺.

-   (11)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline

Melting point: 162° C.–164° C.; R_(f) value: 0.55 (silica gel, ethylacetate/methanol=9:1); mass spectrum (ESI⁻): m/z=387, 389 [M−H]⁻.

-   (12)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline

R_(f) value: 0.27 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁻): m/z=373, 375 [M−H]⁻.

-   (13)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(tetrahydropyran-4-yl)oxy]quinazoline

R_(f) value: 0.41 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁻): m/z=387, 389 [M−H]⁻.

-   (14)    6-Amino-4-[(R)-(1-phenylethyl)amino]-7-[2-(azetidin-1-yl)-ethoxy]quinazoline

R_(f) value: 0.37 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=364[M+H]⁺.

-   (15)    6-Amino-4-[(R)-(1-phenylethyl)amino]-7-[2-(4-methyl-perhydro-1,4-diazepin-1-yl)-ethoxy]quinazoline

R_(f) value: 0.10 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:1); mass spectrum (ESI⁺): m/z=421 [M+H]⁺.

-   (16)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-perhydro-1,4-diazepin-1-yl)propyloxy]quinazoline

R_(f) value: 0.09 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=459, 461[M+H]⁺.

-   (17)    6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]quinazoline

R_(f) value: 0.11 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=402, 404[M+H]⁺.

EXAMPLE II4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-nitroquinazoline

To a solution of 1.45 g of 3-(1-methylpiperidin-4-yl)propan-l-ol in 40ml of tetrahydrofuran are added 360 mg of sodium hydride. The whitesuspension formed is stirred for 15 minutes at 65° C., cooled and mixedwith 1.45 g of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline,whereupon the mixture suddenly turns dark red. The reaction mixture isstirred first for 10 minutes at ambient temperature, then for 45 minutesat 65° C. As the reaction is not yet complete, a further 150 mg ofsodium hydride are added and the mixture is stirred for a further 45minutes at 65° C. The solvent is distilled off using a rotary evaporatorand the brown residue is stirred with 50 ml of ice water. The aqueousphase is extracted with methylene chloride. The combined extracts arewashed with water, dried over sodium sulfate and concentrated byevaporation. The crude product is purified by chromatography over asilica gel column with methylene chloride/methanol/concentrated ammoniasolution (90:10:0.05). Yield: 1.30 g of (65% of theory); R_(f) value:0.28 (silica gel, methylene chloride/methanol/concentrated aqueousammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺.

The following compounds are prepared analogously to Example II:

-   (1)    4-[(3-Bromophenyl)amino]-7-[2-(1-methylpiperidin-4-yl)ethoxy]-6-nitroquinazoline

Melting point: 152° C.; mass spectrum (ESI⁺): m/z=486, 488 [M+H]⁺.

-   (2)    4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]-6-nitroquinazoline

Melting point: 205° C.–207° C.; mass spectrum (ESI⁺): m/z=472, 474[M+H]⁺.

-   (3)    4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]-6-nitroquinazoline

Melting point: 219° C.; mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺.

-   (4)    4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.Melting point: 211° C.–213° C.; mass spectrum (ESI⁺): m/z=389, 391[M+H]⁺.

-   (5)    4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclobutyloxy-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.Melting point: 235° C.; R_(f) value: 0.65 (silica gel, cyclohexane/ethylacetate=3:4).

-   (6)    4-[(3-Chloro-4-fluorophenyl)amino]-7-cyclopentyloxy-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.Melting point: 230° C.; mass spectrum (ESI⁺): m/z=403, 405 [M+H]⁺.

-   (7) 4-[(R)-(1-Phenylethyl)amino]-7-cyclobutyloxy-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.Melting point: 108° C.–1 10° C.; R_(f) value: 0.54 (silica gel, ethylacetate).

-   (8)    4-[(R)-(1-Phenylethyl)amino]-7-cyclopropylmethoxy-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.Melting point: 155° C.; R_(f) value: 0.24 (silica gel, cyclohexane/ethylacetate=1:1).

-   (9) 4-[(R)-(1-Phenylethyl)amino]-7-cyclopentyloxy-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.R_(f) value: 0.24 (silica gel, petroleum ether/ethyl acetate=1:1); massspectrum (ESI⁺): m/z=379 [M+H]⁺.

-   (10)    4-[(3-Chloro-4-fluorophenyl)amino]-6-nitro-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁻): m/z=474, 476[M+H]⁺.

-   (11)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[(tetrahydrofuran-2-yl)methoxy]-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.R_(f) value: 0.47 (silica gel, ethyl acetate); mass spectrum (ESI⁻):m/z=417, 419 [M−H]⁻.

-   (12)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.R_(f) value: 0.45 (silica gel, ethyl acetate); mass spectrum (ESI⁻):m/z=403, 405 [M−H]⁻.

-   (13)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[(tetrahydropyran-4-yl)oxy]-6-nitroquinazoline

Carried out in dimethylformamide with potassium tert-butoxide as base.R_(f) value: 0.41 (silica gel, ethyl acetate); mass spectrum (ESI⁻):m/z=417, 419 [M−H]⁻.

-   (14)    4-[(R)-(1-Phenylethyl)amino]-7-[2-(tetrahydropyran-2-yloxy)ethoxy]-6-nitroquinazoline

R_(f) value: 0.12 (silica gel, cyclohexane/ethyl acetate=1:1); massspectrum (ESI⁺): m/z=439 [M+H].

-   (15)    4-[(3-Chloro-4-fluorophenyl)amino]-7-{3-[(tert-butyldimethylsilyl)oxy]propyloxy}-6-nitroquinazoline    (carried out in dimethylformamide with potassium tert-butoxide as    base)

R_(f) value: 0.87 silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=507, 509[M+H]⁺.

EXAMPLE III 4-[(R)-(1-Phenylethyl)amino]-6-nitro-7-fluoroquinazoline

A solution of 74 ml of (R)-1-phenylethylamine in 100 ml of dioxane isdropped into 108.8 g of 4-chloro-6-nitro-7-fluoro-quinazoline in 800 mlof methylene chloride with cooling. The reaction mixture is washed withwater after stirring overnight at room temperature, the organic phase isseparated, dried and evaporated. The obtained residue is purified bychromatography over a silica gel column (petroleum ether/ethylacetate=1:1). Yield: 52.9 g (35% of theory); melting point: 203° C.;mass spectrum (ESI⁺): m/z=313 [M+H]⁺.

EXAMPLE IV4-[(R)-(1-Phenylethyl)amino]-7-[2-(azetidin-1-yl)ethoxy]-6-nitroquinazoline

221 mg of dried potassium carbonate and 50 mg of sodium iodide weregiven to 600 mg of4-[(R)-(1-phenylethyl)amino]-7-[2-methanesulfonyloxyethoxy]-6-nitroquinazolineand 0.34 ml of azetidine in 5.0 ml of acetonitrile. The reaction mixturewas heated up to 70° C. with stirring. Subsequently 3 ml of acetonitrilewere added after one hour and the mixture was stirred for further about40 hours at 70° C. The solvent was removed in vacuo and the obtainedresidue was mixed with ice water. The precipitate was suction filteredand dried. The aqueous phase was extracted with methylene chloride andevaporated. The combined precipitates were dissolved in ethyl acetateand stirred together with a little of silica gel and 120 mg of charcoalfor further purification. The obtained suspension was filtered andevaporated yielding a yellow resin. Yield: 518 mg (95% of theory); R_(f)value: 0.40 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution 90:10:0.1); mass spectrum (ESI⁺): m/z=394[M+H]⁺.

The following compounds were obtained analogously to Example IV:

-   (1)    4-[(R)-(1-Phenylethyl)amino]-7-[2-(4-methyl-perhydro-1,4-diazepin-1-yl)-ethoxy]-6-nitroquinazoline

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=451[M+H]⁺.

-   (2)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-perhydro-1,4-diazepin-1-yl)    propyloxy]-6-nitroquinazoline

R_(f) value: 0.34 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=80:20:0.1); mass spectrum (ESI⁺): m/z=489, 491[M+H]⁺.

-   (3)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]-6-nitroquinazoline

R_(f) value: 0.23 silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=432, 434[M+H]⁺.

EXAMPLE V4-[(R)-(1-Phenylethyl)amino]-7-[2-(methanesulfonyloxy)ethoxy]-6-nitroquinazoline

A solution of 1.79 ml methanesulfonic acid chloride in 10 ml ofmethylene chloride was dropped into a mixture of 8.08 g of4-[(R)-(1-phenylethyl)amino]-7-(2-hydroxyethoxy)-6-nitroquinazoline and4.53 ml of ethyl-diisopropylamine in 90 ml of methylene chloride withice cooling. The reaction mixture was stirred about one hour at roomtemperature whereby further 0.4 ml of methanesulfonic acid chloride and0.5 ml of ethyldiisopropylamine were added to complete the reaction.Subsequently the reaction mixture was mixed with ice water and stirredafter addition of saturated aqueous sodium carbonate solution. Theorganic phase was separated, washed with water, dried over magnesiumsulfate and evaporated. The obtained dark resinous residue wascrystallized by stirring with little tert-butyl methyl ether, suctionfiltered and dried in an exsiccator. Yield: 9.72 g (99% of theory);melting point: 128° C.–134° C.; mass spectrum (ESI⁻): m/z=431 [M−H]⁻.

The following compound was obtained analogously to Example V:

-   (1)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(methanesulfonyloxy)propyloxy]-6-nitroquinazoline

R_(f) value: 0.75 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=471, 473[M+H]⁺.

EXAMPLE VI4-[(R)-(1-Phenylethyl)amino]-7-(2-hydroxyethoxy)-6-nitroquinazoline

120 ml of methanol and 2 ml of concentrated hydrochloric acid were givento 8.05 g of 4-[(R)-(1-Phenylethyl)amino]-7-[2-(tetrahydropyran-2-yloxy)ethoxy]-6-nitroquinazoline. Afterstirring for 1.5 hours at 50° C. the reaction mixture was neutralizedwith concentrated aqueous sodium carbonate solution and evaporated. Thesolid residue was dissolved in ethyl acetate and the obtained solutionwas washed with water, with concentrated aqueous sodium chloridesolution, dried over magnesium sulfate solution and evaporated. Theobtained yellow residue was stirred with 20 ml of tert-butyl methylether, suction filtered and dried in an exsiccator. Yield: 4.53 g (91%of theory); melting point: 192° C.–194° C.; mass spectrum (ESI⁻):m/z=353 [M−H]⁻.

EXAMPLE VII4-[(3-Chloro-4-fluorophenyl)amino]-7-(3-hydroxypropyloxy-6-nitroquinazoline

Prepared from4-[(3-Chloro-4-fluorophenyl)amino]-7-{3-[(tert-butyl-dimethylsilyl)oxy]propyloxy}-6-nitroquinazolineby splitting off the protective silyl group with tetrabutyl ammoniumfluoride in tetrahydrofuran. Yield: 94% of theory; R_(f) value: 0.61(silica gel, methylene chloride/methanol/concentrated aqueous ammoniasolution=90:10:0.1); mass spectrum (ESI⁻): m/z=391, 393 [M−H]⁻.

Preparation of the end products:

EXAMPLE 14-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline

To a solution of 300 mg of6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazolinein 7 ml of dichloromethane are added 0.28 ml of triethylamine. Thereaction mixture is cooled to about −10° C. in an ice/sodium chloridecooling bath. Then a solution of 59 μl of acrylic acid chloride in 1 mlof tetrahydrofuran is added dropwise within 10 minutes. The cooling bathis removed and the mixture is stirred for a further 15 minutes atambient temperature. For working up, the reaction mixture is poured onto 20 ml of ice water and mixed with 2–3 ml of 2 N sodium hydroxidesolution, whereupon a light-colored precipitate is formed. Theprecipitate is suction filtered, washed with cold water and dissolved indichloromethane. The solution is dried over sodium sulfate andconcentrated by evaporation. The resin-like crude product is purified bychromatography over a silica gel column with methylenechloride/methanol/concentrated ammonia solution (90:10:0.5). Yield: 118mg (35% of theory); R_(f) value: 0.35 (silica gel, methylenechloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); massspectrum (ESI⁺): m/z=524, 526 [M+H]⁺.

The following compounds are obtained analogously to Example 1:

-   (1)    4-[(3-Bromophenyl)amino]-7-[2-(1-methylpiperidin-4-yl)ethoxy]-6-[(vinylcarbonyl)amino]quinazoline

Melting point: 129° C.; mass spectrum (ESI⁺): m/z=510, 512 [M+H]⁺.

-   (2)    4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]-6-[(vinylcarbonyl)amino]quinazoline

Melting point: 174° C.; mass spectrum (ESI⁺): m/z=496, 498 [M+H]⁺.

-   (3)    4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]-6-[(vinylcarbonyl)amino]quinazoline

Melting point: 166° C.; mass spectrum (ESI⁺): m/z=482, 484 [M+H]⁺.

-   (4)    4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)oxy]-6-[(1-oxo-2-buten-1-yl)amino]quinazoline

R_(f) value: 0.67 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=40:10:0.5); mass spectrum (ESI⁺): m/z=496, 498[M+H]⁺.

-   (5)    4-[(3-Bromophenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]-6-[(1-oxo-2-buten-1-yl)amino]quinazoline

R_(f) value: 0.45 (aluminium oxide, activity III; ethylacetate/methanol=4:1); mass spectrum (EI): m/z=509, 511 [M]⁺.

-   (6)    4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(3-ethoxycarbonyl-1-oxo-2-propen-1-yl)amino]quinazoline

R_(f) value: 0.28 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=596, 598[M+H]⁺.

-   (7)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline

R_(f) value: 0.33 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=498, 500[M+H]⁺.

-   (8)    4-[(R)-(1-Phenylethyl)amino]-7-[2-(azetidin-1-yl)-ethoxy]-6-[(vinylcarbonyl)amino]quinazoline

R_(f) value: 0.60 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁻): m/z=416[M−H]⁻.

-   (9)    4-[(R)-(1-Phenylethyl)amino]-7-[2-(4-methyl-perhydro-1,4-diazepin-1-yl)-ethoxy]-6-[(vinylcarbonyl)amino]quinazoline

R_(f) value: 0.37 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁻): m/z=473[M−H]⁻.

-   (10)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-perhydro-1,4-diazepin-1-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline

R_(f) value: 0.29 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁺): m/z=513, 515[M+H]⁺.

-   (11)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline

R_(f) value: 0.39 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=90:10:0.1); mass spectrum (ESI⁻): m/z=454, 456[M−H]⁻.

EXAMPLE 24-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-oxo-2,4-hexadien-1-yl)amino]quinazoline

To 31 mg of sorbic acid in 1 ml of tetrahydrofuran are added 40 μl ofisobutyl chloroformate followed by 45 μl of N-methylmorpholine whilstcooling with an ice bath. The white suspension is stirred for oneminute, then a solution of 100 mg of6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazolinein 1.5 ml of pyridine is added. The ice bath is removed and the reactionmixture is stirred overnight. For working up, it is poured onto 20 ml ofice water, stirred for 30 minutes and adjusted to pH 9–10 with a fewdrops of 2 N sodium hydroxide solution. The aqueous phase is extractedwith methylene chloride, the combined organic phases are dried oversodium sulfate and concentrated by evaporation. The resin-like crudeproduct is purified by chromatography over an aluminium oxide column(activity III) with methylene chloride/methanol (99.5:0.5). Yield: 62 mg(52% of theory); R_(f) value: 0.29 (aluminium oxide, activity III;methylene chloride/methanol=98:2); mass spectrum (EI): m/z=563, 565[M]⁺.

The following compounds are obtained analogously to Example 2:

-   (1)    4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-oxo-2-buten-1-yl)amino]quinazoline

R_(f) value: 0.26 (aluminium oxide, activity III; methylenechloride/methanol=98:2); mass spectrum (ESI⁺): m/z=538, 540 [M+H]⁺.

-   (2)    4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(3-phenyl-1-oxo-2-propen-1-yl)amino]quinazoline

R_(f) value: 0.26 (aluminium oxide, activity III; methylenechloride/methanol=98:2); mass spectrum (EI): m/z=599, 601 [M]⁺.

-   (3)    4-[(3-Bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]-6-[(1-oxo-2-butyn-1-yl)amino]quinazoline

R_(f) value: 0.40 (aluminium oxide, activity III; methylenechloride/methanol=98:2); mass spectrum (ESI⁺): m/z=536, 538 [M+H]⁺.

EXAMPLE 34-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

To a solution of 640 mg of 4-bromo-2-butenoic acid in 10 ml of methylenechloride are added, at ambient temperature, 0.67 ml of oxalyl chlorideand one drop of dimethylformamide. The reaction mixture is stirred forabout another half hour at ambient temperature, until the development ofgas has ceased. The acid chloride formed is substantially freed fromsolvent in vacuo using a rotary evaporator. Then the crude product isdissolved in 10 ml of methylene chloride and added dropwise, whilstcooling with an ice bath, to a mixture of 1.00 g of6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazolineand 1.60 ml of Hüinig base in 50 ml of tetrahydrofuran. The reactionmixture is stirred for 1.5 hours in an ice bath and for a further 2hours at ambient temperature. Then 2.90 ml of diethylamine are added andthe mixture is stirred for 2.5 days at ambient temperature. To work itup, the reaction mixture is filtered and the filtrate is concentrated byevaporation. The filter residue is purified by chromatography over asilica gel column with ethyl acetate/methanol (19:1). Yield: 550 mg (40%of theory); melting point: 114° C.; mass spectrum (ESI⁺): m/z=498, 500[M+H]⁺.

The following compounds are obtained analogously to Example 3:

-   (1)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.53 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁻): m/z=510, 512 [M−H]⁻.

-   (2)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-ethylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.44 (silica gel, ethyl acetate/methanol/concentratedaqueous ammonia solution=9:1:0.1); mass spectrum (EI): m/z=538, 540[M]⁺.

-   (3)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,6-dimethyl-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

Melting point: 160° C.; mass spectrum (ESI⁺): m/z=540, 542 [M+H]⁺.

-   (4)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

Melting point: 137° C.; mass spectrum (ESI⁺): m/z=470, 472 [M+H]⁺.

-   (5)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(1-oxido-thiomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

Melting point: 239° C.; mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺.

-   (6)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline

R_(f) value: 0.45 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=512, 514 [M+H]⁺.

-   (7)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline

Melting point: 143° C.; R_(f) value: 0.45 (silica gel, ethylacetate/methanol=9:1).

-   (8)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline

Melting point: 111° C.; R_(f) value: 0.21 (silica gel, ethylacetate/methanol=9:1).

-   (9)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline

Melting point: 105° C.; R_(f) value: 0.23 (silica gel, ethylacetate/methanol=9:1).

-   (10)    4-[(R)-(1-Phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline

R_(f) value: 0.33 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=488 [M+H]⁺.

-   (11)    4-[(R)-(1-Phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino    }-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.37 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=488 [M+H]⁺.

-   (12)    4-[(R)-(1-Phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline

R_(f) value: 0.35 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=502 [M+H]⁺.

-   (13)    4-[(R)-(1-Phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline

R_(f) value: 0.26 (silica gel, ethyl acetate/methanol=4:1); massspectrum (ESI⁺): m/z=474 [M+H]⁺.

-   (14)    4-[(R)-(1-Phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline

R_(f) value: 0.31 (silica gel, ethyl acetate/methanol=4:1); massspectrum (ESI⁺): m/z=488 [M+H]⁺.

-   (15)    4-[(R)-(1-Phenylethyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.15 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=474 [M+H]⁺.

-   (16)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(1-methylpiperidin-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.28 (silica gel, ethyl acetate/methanol/concentratedaqueous ammonia solution=80:20:2); mass spectrum (ESI⁺): m/z=553, 555[M+H]⁺.

-   (17)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-2-methoxymethylpyrrolidin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.33 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=540, 542 [M+H]⁺.

-   (18)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-2-methoxymethylpyrrolidin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

Melting point: 120° C.; mass spectrum (ESI⁺): m/z=540, 542 [M+H]⁺.

-   (19)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[bis-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.51 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=558, 560 [M+H]⁺.

-   (20)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-ethyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.33 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=528, 530 [M+H]⁺.

-   (21)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.22 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=510, 512 [M+H]⁺.

-   (22)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.21 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=524, 526 [M+H]⁺.

-   (23)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(pyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.10 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁺): m/z=496, 498 [M+H]⁺.

-   (24)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylmethylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

Melting point: 117° C.; mass spectrum (ESI⁺): m/z=565, 567 [M+H]⁺.

-   (25)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

Melting point: 108° C.–110° C.; R_(f) value: 0.27 (silica gel, ethylacetate/methanol=9:1).

-   (26)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.29 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁻): m/z=538, 540 [M−H]⁻.

-   (27)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(cis-2,6-dimethylpiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.27 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁻): m/z=536, 538 [M−H]⁻.

-   (28)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,5-dimethylpyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.36 (silica gel, ethyl acetate/methanol=9:1); massspectrum (ESI⁻): m/z=522, 524 [M−H]⁺.

-   (29)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline

R_(f) value: 0.35 (silica gel, ethyl acetate/methanol/concentratedaqueous ammonia solution=9:1:0.1); mass spectrum (ESI⁻): m/z 526, 528[M−H]⁻.

-   (30)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofaran-3-yl)oxy]quinazoline

Melting point: 119° C.; mass spectrum (ESI⁻): m/z=512, 514 [M−H]⁻.

-   (31)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-diethylaminomethylpiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.20 (silica gel, methylene chloride/methanol=9:1); massspectrum (ESI⁻): m/z=593, 595 [M−H]⁻.

-   (32)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-methyl-N-cyclopropylmethyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.73 (silica gel, methylene chloride/methanol=9:1); massspectrum (ESI⁺): m/z=510, 512 [M+H]⁺.

-   (33)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxypropyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

The N-methyl-N-(2-methoxypropyl)amine used was prepared by reaction of2-methoxypropionic acid chloride with methylamine and subsequentreduction with lithium aluminium hydride; melting point: 123° C.–125°C.; R_(f) value: 0.66 (silica gel, methylene chloride/methanol=9:1).

-   (34)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(3-methoxypropyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.66 (silica gel, methylene chloride/methanol=9:1); massspectrum (ESI⁺): m/z=528, 530 [M+H]⁺.

-   (35)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methoxypiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

Melting point: 129° C.–130° C.; R_(f) value: 0.20 (silica gel, ethylacetate/methanol=9:1); mass spectrum (ESI⁻): m/z=538, 540 [M−H]⁻.

-   (36)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-hydroxypiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/concentratedaqueous ammonia solution=9:1:0.1); mass spectrum (ESI⁻): m/z=524, 526[M−H]⁻.

-   (37)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(diethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline

R_(f) value: 0.47 (silica gel, methylene chloride/methanol=9:1); massspectrum (ESI⁻): m/z=528, 530 [M−H]⁻.

-   (38)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

Melting point: about 145° C. (decomp.); R_(f) value: 0.23 (silica gel,methylene chloride/methanol=15:1); Mass spectrum (ESI⁺): m/z=540, 542[M+H]⁺.

-   (39)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

The starting N-methyl-N-(3-tetrahydrofuranyl)amine was prepared byreaction of tetrahydrofaran-3-carboxylic acid with diphenyl phosphonateazide in benzyl alcohol and subsequent reduction of the obtained3-(benzyloxycarbonylamino)tetrahydrofuran with lithium aluminiumhydride. Melting point: 157° C.–159° C.; R_(f) value: 0.23 (silica gel,methylene chloride/methanol=15:1); mass spectrum (ESI⁺): m/z=526, 528[M+H]⁺.

-   (40)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(1-methoxy-2-propyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline

The starting N-methyl-N-(1-methoxy-2-propyl)amine was prepared byreductive amination of methoxyacetone with methylamine hydrochloride andsodium triacetoxyborohydride in the presence of sodium acetate. Thereaction was carried out in tetrahydrofuran. R_(f) value: 0.38 (silicagel, ethyl acetate/methanol=9:1); mass spectrum (ESI⁺): m/z 528, 530[M+H]⁺.

The following compounds may also be obtained analogously to the aboveExamples and other methods known from the literature:

-   (1)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (2)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dibutylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (3)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (4)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,6-dimethylmorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (5)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (6)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylmethylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (7)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (8)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylsulfonylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (9)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-acetylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (10)    4-[(3-Chloro-4-fluorophenyl)amino]-6-[(4-{4-[(N,N-di-methylamino)carbonyl]piperazin-1-yl}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline-   (11)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(pyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (12)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (13)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropylmethyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (14)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (15)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (16)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (17)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (18)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylpiperazin-1-yl)-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (19)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methylsulfonylpiperazin-1-yl)-1-oxo-2-butyn-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (20)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1,4-dioxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (21)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(3-N,N-dimethylamino-propan-1-yl)amino]-1,4-dioxo-2-buten-1-yl}amino]-7-cyclopropylmethoxyquinazoline-   (22)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({2-[(N,N-diethylamino)methyl]-1-oxo-2-propen-1-yl}amino]-7-cyclopropylmethoxyquinazoline-   (23)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methoxymethylpyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline-   (24)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (25)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (26)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutylmethoxyquinazoline-   (27)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentylmethoxyquinazoline-   (28)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclohexylmethoxyquinazoline-   (29)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(2-cyclopropylethoxy)quinazoline-   (30)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(3-cyclopropylpropyloxy)quinazoline-   (31)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(tetrahydrofuran-3-yl)piperidin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (32)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(morpholin-4-yl)piperidin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (33)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(tetrahydrofuran-3-yl)piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (34)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(tetrahydrofuran-2-ylmethyl)piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (35)    4-[(3-Chloro-4-fluorophenyl)amino]-6-[(4-{N-methyl-N-[1-(tetrahydrofuran-3-yl)piperidin-4-yl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline-   (36)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-2-methoxymethylpyrrolidin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (37)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-2-methoxymethylpyrrolidin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (38)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[bis-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (39)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (40)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(1-methoxy-2-propyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (41)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(1-methoxy-2-propyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (42)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(1-methoxy-2-propyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (43)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxypropyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (44)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(3-methoxypropyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (45)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (46)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (47)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-3-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (48)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (49)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydropyran-4-yl)amino]-1-oxo-2-buten-1-yl    }amino)-7-cyclobutyloxyquinazoline-   (50)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (51)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-cyclopropylmethylpiperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (52)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (53)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropylmethyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (54)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline-   (55)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(R)-N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline-   (56)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[(S)-N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclobutyloxyquinazoline-   (57)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(pyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (58)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (59)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,5-dimethylpyrrolidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (60)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(piperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (61)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2-methylpiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (62)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(2,6-dimethylpiperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (63)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-hydroxy-piperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (64)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(4-methoxy-piperidin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (65)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[4-(2-methoxyethyl)piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclobutyloxyquinazoline-   (66)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-morphoin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (67)    4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(3,5-dimethyl-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline-   (68)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-3-yloxy)quinazoline-   (69)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydropyran-4-yloxy)quinazoline-   (70)    4-[(3-Chloro-4-fluorophenyl)amino]-6-({4-[N-methyl-N-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-(tetrahydrofuran-2-ylmethoxy)quinazoline-   (71)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(azetidin-1-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline-   (72)    4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(4-methyl-homopiperazin-1-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline.

EXAMPLE 4

Coated tablets containing 75 mg of active substance 1 tablet corecontains: active substance  75.0 mg calcium phosphate  93.0 mg cornstarch  35.5 mg polyvinylpyrrolidone  10.0 mghydroxypropylmethylcellulose  15.0 mg magnesium stearate  1.5 mg 230.0mg

Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks 13 mm in diameter areproduced in a tablet-making machine and these are then rubbed through ascreen with a mesh size of 1.5 mm using a suitable machine and mixedwith the rest of the magnesium stearate. This granulate is compressed ina tablet-making machine to form tablets of the desired shape. Weight ofcore: 230 mg; die: 9 mm, convex. The tablet cores thus produced arecoated with a film consisting essentially ofhydroxypropylmethylcellulose. The finished film-coated tablets arepolished with beeswax. Weight of coated tablet: 245 mg.

EXAMPLE 5

Tablets containing 100 mg of active substance Composition: 1 tabletcontains: active substance 100.0 mg lactose  80.0 mg corn starch  34.0mg polyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg 220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets. Weight of tablet: 220 mg;diameter: 10 mm, biplanar, facetted on both sides and notched on oneside.

EXAMPLE 6

Tablets containing 150 mg of active substance Composition: 1 tabletcontains: active substance  50.0 mg powdered lactose  89.0 mg cornstarch  40.0 mg colloidal silica  10.0 mg polyvinylpyrrolidone  10.0 mgmagnesium stearate  1.0 mg 300.0 mg

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture. Weight of tablet: 300 mg; die: 10 mm, flat.

EXAMPLE 7

Hard gelatine capsules containing 150 mg of active substance 1 capsulecontains: active substance 50.0 mg corn starch (dried) approx. 80.0 mglactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx.420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules. Capsule filling: approx. 320 mg; capsule shell: size1 hard gelatine capsule.

EXAMPLE 8

Suppositories containing 150 mg of active substance 1 suppositorycontains: active substance   150.0 mg polyethyleneglycol 1500   550.0 mgpolyethyleneglycol 6000   460.0 mg polyoxyethylene sorbitan monostearate  840.0 mg 2,000.0 mg

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmolds.

EXAMPLE 9

Suspension containing 50 mg of active substance 100 ml of suspensioncontain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 gmethyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavoring 0.30 gdist. water ad 100 ml

Preparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavoring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air. 5 ml ofsuspension contain 50 mg of active substance.

EXAMPLE 10

Ampoules containing 10 mg active substance Composition: active substance10.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

EXAMPLE 11

Ampoules containing 50 mg of active substance Composition: activesubstance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilled waterad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

EXAMPLE 12

Capsules for powder inhalation containing 5 mg of active substance 1capsule contains: active substance  5.0 mg lactose for inhalation 15.0mg 20.0 mg

Preparation:

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg). Weight of capsule: 70.0 mg; size of capsule=3.

EXAMPLE 13

Solution for inhalation for hand-held nebulizers containing 2.5 mgactive substance 1 spray contains: active substance   2.500 mgbenzalkonium chloride   0.001 mg 1N hydrochloric acid q.s. ethanol/water(50/50) ad 15.000 mg

Preparation:

The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1Nhydrochloric acid. The resulting solution is filtered and transferredinto suitable containers for use in hand-held nebulizers (cartridges).Contents of the container: 4.5 g.

1. A quinazoline compound of formula

wherein R_(a) denotes a hydrogen atom or a C₁₋₄-alkyl group, R_(b)denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenylnucleus is substituted in each case by the groups R₁ to R₃, whilst R₁and R₂, which may be identical or different, in each case denote ahydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₄-alkyl,hydroxy, C₁₋₄-alkoxy, C₃₋₆-cycloalkyl, C₄₋₆-cycloalkoxy, C₂₋₅-alkenyl orC₂₋₅-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, aC₃₋₅-alkenyloxy or C₃₋₅-alkynyloxy group, whilst the unsaturated moietymay not be linked to the oxygen atom, a C₁₋₄-alkylsulfenyl,C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl, C₁₋₄-alkylsulfonyloxy,trifluoromethylsulfenyl, trifluoromethylsulfinyl ortrifluoromethylsulfonyl group, a methyl or methoxy group substituted by1 to 3 fluorine atoms, an ethyl or ethoxy group substituted by 1 to 5fluorine atoms, a cyano or nitro group or an amino group optionallysubstituted by one or two C₁₋₄-alkyl groups, wherein the substituentsmay be identical or different, or R₁ together with R₂, if they are boundto adjacent carbon atoms, denote a —CH═CH—CH═CH group and R₃ denotes ahydrogen, fluorine, chlorine or bromine atom, a C₁₋₄-alkyl,trifluoromethyl or C₁₋₄-alkoxy group, X denotes a nitrogen atom, Adenotes an imino group optionally substituted by a C₁₋₄-alkyl group, Bdenotes a carbonyl group, C denotes a —CH═C═CH—, >C═CH₂ or —CH═CH— groupwhich may be substituted in each case by one or two methyl groups or bya trifluoromethyl group, an —C≡C— group or a —CH═CH—CH═CH— groupoptionally substituted by 1 to 4 methyl groups or by a trifluoromethylgroup, D denotes an alkylene group wherein the alkylene moiety contains1 to 8 carbon atoms and additionally 1 to 4 hydrogen atoms in thealkylene moiety may be replaced by fluorine atoms, E denotes an amino,C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-amino group wherein the alkylmoieties may be identical or different, a C₂₋₄-alkylamino group whereinthe alkyl moiety is substituted in β-, γ-, or δ-position with regard tothe nitrogen atom of the amino group by the group R₅, whilst R₅ denotesa hydroxy, C₁₋₄-alkoxy, amino, C₁₋₄-alkylamino or di-(C₁₋₄-alkyl)-aminogroup, an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein theC₂₋₄-alkyl moiety is substituted in β-, γ-, or δ-position with regard tothe nitrogen atom of the amino group by the group R₅, whilst R₅ is ashereinbefore defined, a di-(C₂₋₄-alkyl)-amino group wherein the twoC₂₋₄-alkyl moieties are substituted in each case in β-, γ-, orδ-position with regard to the nitrogen atom of the amino group by thegroup R₅, whilst the substituents may be identical or different and R₅is as hereinbefore defined, a C₃₋₇-cycloalkylamino orC₃₋₇-cycloalkyl-C₁₋₃-alkylamino group wherein in each case the nitrogenatom may be substituted by a further C₁₋₄-alkyl group, R_(c) denotes aC₄₋₇-cycloalkoxy or C₃₋₇-cycloalkyl-C₁₋₆-alkoxy group wherein thecycloalkyl moiety in each case may be substituted by a C₁₋₃-alkyl,hydroxy, C₁₋₄-alkoxy, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,hydroxy-C₁₋₂-alkyl, C₁₋₄-alkoxy-C₁₋₂-alkyl, amino-C₁₋₂-alkyl,C₁₋₄-alkylamino-C₁₋₂-alkyl, or di-(C₁₋₄-alkyl)-amino-C₁₋₂-alkyl group,whilst the abovementioned monosubstituted cycloalkyl moieties mayadditionally be substituted by a C₁₋₃-alkyl group, whilst by the arylmoieties mentioned in the definition of the abovementioned groups ismeant a phenyl group which in each case may be monosubstituted by R₇,mono-, di- or trisubstituted by R₈ or monosubstituted by R₇ andadditionally mono- or disubstituted by R₈, wherein the substituents maybe identical or different and R₇ denotes a cyano, carboxy,C₁₋₄-alkoxycarbonyl, aminocarbonyl, C₁₋₄-alkylaminocarbonyl,di-(C₁₋₄-alkyl)-aminocarbonyl, C₁₋₄-alkylsulfenyl, C₁₋₄-alkylsulfinyl,C₁₋₄-alkylsulfonyl, hydroxy, C₁₋₄-alkylsulfonyloxy, trifluoromethyloxy,nitro, amino, C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino,C₁₋₄-alkyl-carbonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonylamino,C₁₋₄-alkylsulfonylamino, N-(C₁₋₄-alkyl)-C₁₋₄-alkylsulfonylamino,aminosulfonyl, C₁₋₄-alkylaminosulfonyl or di-(C₁₋₄-alkyl)-aminosulfonylgroup, and R₈ denotes a fluorine, chlorine, bromine or iodine atom, aC₁₋₄-alkyl, trifluoromethyl or C₁₋₄-alkoxy group or two groups R₈, ifthey are bound to adjacent carbon atoms, together denote a C₃₋₅-alkyleneor 1,3-butadien-1,4-ylene group, or the tautomers, or stereoisomers orpharmaceutically acceptable salts thereof.
 2. The quinazoline of formulaI according to claim 1, wherein R_(a) denotes a hydrogen atom, R_(b)denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenylnucleus is substituted in each case by the groups R₁ to R₃, whilst R₁and R₂, which may be identical or different, in each case denote ahydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₄-alkyl,hydroxy, C₁₋₄-alkoxy, C₃₋₆-cycloalkyl, C₄₋₆-cycloalkoxy, C₂₋₅-alkenyl orC₂₋₅-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, amethyl or methoxy group substituted by 1 to 3 fluorine atoms, a cyano ornitro group and R₃ denotes a hydrogen, fluorine, chlorine or bromineatom, a C₁-alkyl, trifluoromethyl or C₁₋₄-alkoxy group, X denotes anitrogen atom, A denotes an imino group, B denotes a carbonyl group, Cdenotes a —CH═C═CH—, >C═CH₂ or —CH═CH— group, an —C═C— or —CH═CH—CH═CH—group, D denotes an alkylene group wherein the alkylene moiety in eachcase contains 1 to 4 carbon atoms and additionally 1 to 4 hydrogen atomsin the alkylene moiety may be replaced by fluorine atoms, E denotes adi-(C₁₋₄-alkyl)-amino group wherein the alkyl moieties may be identicalor different, an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein theC₂₋₄-alkyl moiety is substituted in β-, γ-, or δ-position with regard tothe nitrogen atom of the amino group by the group R₅, where R₅ denotes ahydroxy, C₁₋₄-alkoxy or di-(C₁₋₄-alkyl)-amino group, adi-(C₂₋₄-alkyl)-amino group wherein the two C₂₋₄-alkyl moieties in eachcase are substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, wherein thesubstituents may be identical or different and R₅ is as hereinbeforedefined, a C₃₋₇-cycloalkylamino or C₃₋₇-cycloalkyl-C₁₋₃-alkylamino groupwherein in each case the nitrogen atom is substituted by a furtherC₁₋₄-alkyl group, R_(c) denotes a C₄₋₇-cycloalkoxy orC₃₋₇-cycloalkyl-C₁₋₆-alkoxy group wherein the cycloalkyl moiety in eachcase may be substituted by a C₁₋₃-alkyl, hydroxy, C₁₋₄-alkoxy,di-(C₁₋₄-alkyl)-amino, hydroxy-C₁₋₂-alkyl, C₁₋₄-alkoxy-C₁₋₂-alkyl, ordi-(C₁₋₄-alkyl)-amino-C₁₋₂-alkyl group, whilst the abovementionedmonosubstituted cycloalkyl moieties may additionally be substituted by aC₁₋₃-alkyl group, whilst by the aryl moieties mentioned in thedefinition of the abovementioned groups is meant a phenyl group whichmay in each case be monosubstituted by R₇, mono-, di- or trisubstitutedby R₈ or monosubstituted by R₇ and additionally mono- or disubstitutedby R₈, wherein the substituents may be identical or different and R₇denotes a cyano, carboxy, C₁₋₄-alkoxycarbonyl, aminocarbonyl,C₁₋₄-alkylaminocarbonyl, di-(C₁₋₄-alkyl)-aminocarbonyl,C₁₋₄-alkylsulfenyl, C₁₋₄-alkylsulfinyl, C₁₋₄-alkylsulfonyl, hydroxy,C₁₋₄-alkylsulfonyloxy, trifluoromethyloxy, nitro, amino,C₁₋₄-alkylamino, di-(C₁₋₄-alkyl)-amino, C₁₋₄-alkyl-carbonylamino,N-(C₁₋₄-alkyl)-C₁₋₄-alkylcarbonylamino, C₁₋₄-alkylsulfonylamino,N-(C₁₋₄-alkyl)-C₁₋₄-alkylsulfonylamino, aminosulfonyl,C₁₋₄-alkylaminosulfonyl or di-(C₁₋₄-alkyl)-aminosulfonyl group, and R₈denotes a fluorine, chlorine, bromine or iodine atom, a C₁₋₄-alkyl,trifluoromethyl or C₁₋₄-alkoxy group or two groups R₈, if they are boundto adjacent carbon atoms, together denote a C₃₋₅-alkylene or1,3-butadien-1,4-ylene group, or the tautomers, or stereoisomers orpharmaceutically acceptable salts thereof.
 3. The quinazoline of formulaI according to claim 1, wherein R_(a) denotes a hydrogen atom, R_(b)denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenylnucleus is substituted in each case by the groups R₁ and R₂, where R₁and R₂, which may be identical or different, in each case denote ahydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethylor methoxy group, X denotes a nitrogen atom, A denotes an imino group, Bdenotes a carbonyl group, C denotes a —CH═CH— group, an —C═C— or—CH═CH—CH═CH— group, D denotes a C₁₋₄-alkylene group, E denotes adi-(C₁₋₄-alkyl)-amino group wherein the alkyl moieties may be identicalor different, an N-(C₁₋₄-alkyl)-N-(C₂₋₄-alkyl)-amino group wherein theC₂₋₄-alkyl moiety is substituted in β-, γ-, or δ-position with regard tothe nitrogen atom of the amino group by the group R₅, whilst R₅ denotesa hydroxy, C₁₋₃-alkoxy or di-(C₁₋₃-alkyl)-amino group, adi-(C₂₋₄-alkyl)-amino group wherein the two C₂₋₄-alkyl moieties in eachcase are substituted in β-, γ-, or δ-position with regard to thenitrogen atom of the amino group by the group R₅, wherein thesubstituents may be identical or different and R₅ is as hereinbeforedefined, a C₃₋₅-cycloalkylamino or C₃₋₅-cycloalkyl-C₁₋₃-alkylamino groupwherein in each case the nitrogen atom is substituted by a furtherC₁₋₃-alkyl group, R_(c) denotes a C₄₋₇-cycloalkoxy orC₃₋₇-cycloalkyl-C₁₋₄-alkoxy group wherein the cycloalkyl moiety in eachcase may be substituted by a C₁₋₃-alkyl or C₁₋₃-alkoxy group, or thetautomers, or stereoisomers or pharmaceutically acceptable saltsthereof.
 4. The quinazoline of formula I according to claim 1, whereinR_(a) denotes a hydrogen atom, R_(b) denotes a phenyl, benzyl or1-phenylethyl group, whilst the phenyl nucleus is substituted in eachcase by the radicals R₁ and R₂, whilst R₁ and R₂, which may be identicalor different, each denotes a hydrogen, fluorine, chlorine or bromineatom, X denotes a nitrogen atom, A denotes an imino group, B denotes acarbonyl group, C denotes a —CH═CH—, —C≡C— or —CH═CH—CH═CH— group, Ddenotes an C₁₋₃-alkylene group, E denotes a di-(C₁₋₄-alkyl)-amino group,wherein the alkyl moieties may be identical or different, a methylaminoor ethylamino group each substituted at the nitrogen atom by a2-methoxy-ethyl, 1-methoxy-2-propyl, 2-methoxypropyl, 3-methoxypropyl,cyclopropyl or cyclopropylmethyl group, a bis-(2-methoxyethyl)aminogroup, R_(c) denotes a cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy or cyclohexylmethoxy group, a cyclobutyloxy,cyclopentyloxy or cyclohexyloxy group, or the tautomers, orstereoisomers or pharmaceutically acceptable salts thereof.
 5. Thequinazoline of formula I according to claim 1, wherein R_(a) denotes ahydrogen atom, R_(b) denotes a 1-phenylethyl group or a phenyl groupwherein the phenyl nucleus is substituted by the radicals R₁ and R₂,whilst R₁ and R₂, which may be identical or different, each denote ahydrogen, fluorine, chlorine or bromine atom, X denotes a nitrogen atom,A denotes an imino group, B denotes a carbonyl group, C denotes a—CH═CH—, —C≡C— or —CH═CH—CH═CH— group, D denotes a methylene group, Edenotes a dimethylamino, diethylamino, Bis(2-methoxyethyl)amino,N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino,N-methyl-N-cyclopropylamino, N-methyl-N-cyclopropylmethyl-amino,N-methyl-N-(1-methoxy-2-propyl)amino, N-methyl-N-(2-methoxypropyl)aminoor N-methyl-N-(3-methoxypropyl)amino group, R_(c) denotes acyclopropylmethoxy, cyclobutyloxy or cyclopentyloxy group, or thetautomers, or stereoisomers or pharmaceutically acceptable saltsthereof.
 6. The following compound of general formula I according toclaim 1:4-[(3-Chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazolineor a pharmaceutically acceptable salt thereof.
 7. The physiologicallyacceptable salt of a compound according to one of claims 1 to 6 with aninorganic or organic acid or base.
 8. A pharmaceutical compositioncomprising a compound according to claim 7, together with an inertcarrier and with or without a diluent.
 9. A method for treating adisease comprising administering a pharmaceutical composition accordingto claim 8, wherein said disease is selected from the group consistingof: malignant tumors, diseases of the airways and lungs and diseases ofthe gastrointestinal tract and the bile duct and gall bladder.